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@#Programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) signaling pathway has been found capable of affecting anti-tumor immune effect in many malignancies in recent years. Patients who are diagnosed with advanced non-small cell lung cancer (NSCLC) have considerable responses after receving inhibitors against PD-1/PD-L1. This paper reviews the clinical progress of PD-1/PD-L1 inhibitors in the treatment of NSCLC.
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Objective:To analyze, at cellular level, whether the mouse B16-F1 melanoma cells with OAZI-1 overexpression could activate antigen-presenting cells and promote the phagocytotic and antigen-presenting efficiencies of mouse peritoneal macrophage and bone marrow derived DC on tumor cells. Methods:The plasmid pcDNA3. 1(+)/OAZI-1 was transfected into B16-F1 cells by Li-pofectamine2000 reagent. The positive clones with OAZI-1 overexpression ( B16/OAZI-1 ) were identified by Western blot assay and RT-PCR. Macrophages from abdominal cavity and DC from bone marrow were collected from BALB/c mouse. The B16-F1 cells transfected with the pcDNA3. 1(+) (B16/3. 1) were used as the control cells in this experiment. B16-F1 cells and macrophages were co-cultured for 4 h at a 1∶5 ratio and DC were co-cultured with B16-F1 cells at 1∶1 ratio for 4 h. And then the phagocytotic efficiencies were assayed by flow cytometry. DC were co-cultured with B16-F1 cells at 1∶1 ratio for 24 h and then the expression of mature DC surface marker molecules CD40,CD80,CD86 were determined by flow cytometry. The DC activated by the tumor cells were co-cultured with mouse spleen lymphocytes for 24 h, and then IFN-γ content in culture medium was analyzed by ELISA. Results: Phagocytotic assay showed that,compared to the control cells,the OAZI-1 overexpression in B16-F1 cells significantly enhanced the engulfment of B16-F1 cells by macrophages ( 24. 7% vs 53. 9% ) and DC ( 8. 2% vs 13. 8%) . When DC were co-incubated with OAZI-1 overexpressed B16-F1 for 24 h,the expression levels of CD40,CD80,CD86 on the DC surface,which were the molecular markers for matured DC,increased from 24. 2%,20. 8% and 16. 4% to 46. 8%,32. 5% and 36. 1% respectively. Co-culture of tumor-activated DC with the spleen lymphocytes resulted in an increased IFN-γcontent in the culture medium(32. 9 pg/ml vs 15. 1 pg/ml). Conclusion:The tumor cells with OAZI-1 overexpression can be engulfed more efficiently by macrophages and DC. And this process can induce the maturation and activation of DCs. Matured DC could induce T cell activation and then activate the anti-tumor immune response.
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To date, killing cancer cells by cytotoxic drugs is still the mainstay of treatment for different types of cancer. Tumor cells can not be specifically identified by cytotoxic drugs, which may also kill other normal cells. The number of cells in immune system, including lymphocytes and granulocytes, may decrease after chemotherapy with cytotoxic drugs. Therefore, it has been generally recognized for many years that the chemotherapeutic drugs will suppress immune system. However, recent studies have demonstrated that some chemotherapeutic drugs can suppress tumor growth by promoting antitumor immune responses instead of suppressing these responses through modulating the anti-tumor immune responses by changing the immunogenicity of tumor cells, enhancing the immunocompetence of immune-related cells such as dendritic cells, and decreasing the number of immunosuppressive cells. These findings may change the recognization of the role for conventional chemotherapy in anti-tumor treatment, and it will be helpful to optimize the chemotherapy strategies more reasonably. Copyright© 2011 by TUMOR.
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BACKGROUND: As an attempt to develop a strategy to improve the protective immune response to GM-CSF-secreting CT26 (GM-CSF/CT26) tumor vaccine, we have investigated whether the apoptogenic treatment of GM-CSF/CT26 prior to vaccination enhances the induction of anti-tumor immune response in mouse model. METHODS: A carcinogen- induced mouse colorectal tumor, CT26 was transfected with GM-CSF gene using a retroviral vector to generate GM-CSF-secreting CT26 (CT26/GM-CSF). The CT26/GM-CSF was treated with gamma-irradiation or mitomycin C to induce apoptosis and vaccinated into BALB/c mice. After 7 days, the mice were injected with a lethal dose of challenge live CT26 cells to examine the protective effect of tumor vaccination in vivo. RESULTS: Although both apoptotic and necrotic CT26/GM-CSF vaccines were able to enhance anti-tumor immune response, apoptotic CT26/GM-CSF induced by pretreatment with gamma-irradiation (50,000 rads) was the most potent in generating the anti-tumor immunity, and thus 100% of mice vaccinated with the apoptotic cells remained tumor free for more than 60 days after tumor challenge. CONCLUSION: Apoptogenic pretreatment of GM-CSF-secreting CT26 tumor vaccine by gamma-irradiation (50,000 rads) resulted in a significant enhancement in inducing the protective anti-tumor immunity. A rapid induction of apoptosis of CT26/GM-CSF tumor vaccine at the vaccine site might be critical for the enhancement in anti-tumor immune response to tumor vaccine.